Utility of dynamic contrast enhancement for clinically significant prostate cancer detection

Abstract Objective This study aimed to evaluate the association of dynamic contrast enhancement (DCE) with clinically significant prostate cancer (csPCa, Gleason Grade Group ≥2) and compare biparametric magnetic resonance imaging (bpMRI) and multiparametric MRI (mpMRI) nomograms. Subjects/patients and methods We identified a retrospective cohort of biopsy naïve patients who underwent pre‐biopsy MRI separated by individual MRI series from 2018 to 2022. csPCa detection rates were calculated for patients with peripheral zone (PZ) lesions scored 3–5 on diffusion weighted imaging (DWI) with available DCE (annotated as − or +). bpMRI Prostate Imaging Reporting and Data System (PIRADS) (3 = 3−, 3+; 4 = 4−, 4+; 5 = 5−, 5+) and mpMRI PIRADS (3 = 3−; 4 = 3+, 4−, 4+; 5 = 5−, 5+) approaches were compared in multivariable logistic regression models. Nomograms for detection of csPCa and ≥GG3 PCa incorporating all biopsy naïve patients who underwent prostate MRI were generated based on available serum biomarkers [PHI, % free prostate‐specific antigen (PSA), or total PSA] and validated with an independent cohort. Results Patients (n = 1010) with highest PIRADS lesion in PZ were included in initial analysis with 127 (12.6%) classified as PIRADS 3+ (PIRADS 3 on bpMRI but PIRADS 4 on mpMRI). On multivariable analysis, PIRADS 3+ lesions were associated with higher csPCa rates compared to PIRADS 3− (3+ vs. 3−: OR 1.86, p = 0.024), but lower csPCa rates compared to PIRADS DWI 4 lesions (4 vs. 3+: OR 2.39, p < 0.001). csPCa rates were 19% (3−), 31% (3+), 41.5% (4−), 65.9% (4+), 62.5% (5−), and 92.3% (5+). bpMRI nomograms were non‐inferior to mpMRI nomograms in the development (n = 1410) and independent validation (n = 353) cohorts. Risk calculators available at: https://rossnm1.shinyapps.io/MynMRIskCalculator/. Conclusion While DCE positivity by itself was associated with csPCa among patients with highest PIRADS lesions in the PZ, nomogram comparisons suggest that there is no significant difference in performance of bpMRI and mpMRI. bpMRI may be considered as an alternative to mpMRI for prostate cancer evaluation in many situations.

no significant difference in performance of bpMRI and mpMRI.bpMRI may be considered as an alternative to mpMRI for prostate cancer evaluation in many situations.

K E Y W O R D S
diagnosis, dynamic contrast enhancement, nomogram, prostate cancer, prostate MRI, risk stratification

| INTRODUCTION
Pre-biopsy multiparametric prostate magnetic resonance imaging (mpMRI) increases detection of clinically significant prostate cancer (csPCa, defined as ISUP Grade Group ≥2), while avoiding unnecessary biopsies. 1,2However, with an estimated 299 010 new cases of prostate cancer in the United States in 2024, there is increasing demand for diagnostic prostate MRI, which requires significant financial resources, availability of scanners, and qualified readers. 3,4e average cost for mpMRI in the United States is $4400 with significant differences in charges among the facilities within the United States, and also varies widely internationally. 5Universally implementing mpMRI prior to biopsy decision significantly increases cost and could worsen healthcare disparities by creating unequal access to care.
Biparametric MRI (bpMRI) may enhance the accessibility to MRI assessments with reduced examination times, elimination of need for intravenous (IV) access, and avoidance of adverse events associated with gadolinium contrast. 6bpMRI primarily relies on T2 and diffusion weighted imaging (DWI) while omitting the dynamic contrast enhancement (DCE) phase, which is mainly used to upgrade peripheral zone (PZ) Prostate Imaging Reporting and Data System (PIRADS 3) lesions to PIRADS 4 lesions in PIRADS v2.1; DCE can also serve as a back-up sequence if other sequences are inadequate (i.e. in setting of hip replacement) or for evaluation of recurrent prostate cancer. 7Early studies have suggested that bpMRI may be non-inferior to mpMRI in terms of discriminative ability in csPCa detection, questioning the utility of DCE. 8,91][12]

| bpMRI vs. mpMRI nomogram comparison
For bpMRI nomogram generation, we identified and included all biopsy naïve patients presenting for evaluation for elevated prostatespecific antigen (PSA) 2-20 ng/mL receiving mpMRI as previously described for the generation of a mpMRI nomogram. 10The development cohort presented March 2018 to June 2021, and the independent validation cohort presented June 2021 to February 2022.As our objective was to assess performance in all-comers evaluated by MRI for consideration of biopsy, patients with no discrete lesions (PIRADS 1 or 2), highest PIRADS in the transition zone, or deemed to be at low risk with PIRADS 1-3 and selected to forgo biopsy were included as previously described for development of the mpMRI-based nomograms incorporating advanced serum biomarkers when available (PHI and % free PSA). 10 There was a low rate of csPCa detection (2.4% at 23 months follow up) for patients selected to forgo biopsy with PIR-ADS 1-3 (Li et al, under review).

| Screening strategy
Patients in our system are typically screened with PSA, prostate health index (PHI), and mpMRI. 10Biopsy decision is ultimately left to the provider and patient after consideration with other clinical factors.Baseline clinical characteristics, mpMRI reports, and prostate biopsy pathology reports were obtained.Continuous variables were categorized based on prior convention as previously described.

| Prostate biopsy and pathological review
MRI-guided biopsy was performed using cognitive or software fusion (UroNav platform, Phillips, Gainesville, FL).Suspicious lesions were biopsied with 2-5 cores, followed by systematic biopsies.Biopsy procedures were performed with transrectal or freehand transperineal approach with PrecisionPoint system (Perineologic, Cumberland, MD).

| Multivariable logistic regression models
On multivariable analysis, age, Black race, PHI, PSAD, and DCE stratified PIRADS scores were associated with csPCa (Table 2).With multivariable adjustment, PIRADS 3+ lesions were associated with significantly higher csPCa rates compared to PIRADS 3À (OR 1.86, 95% CI 1.08-3.21p = 0.024, respectively), but lower csPCa rates compared to PIRADS DWI 4 lesions (OR 2.39, 95% CI 1.55-3.85,p < 0.001, respectively).DCE was also independently associated with bpMRI offers a faster, more accessible pre-biopsy evaluation in the setting of increased adoption of prostate MRI. 3 Among those with PZ lesions in our large biopsy naïve mpMRI cohort, DCE positivity was associated with csPCa.However, when considering all patients undergoing prostate MRI evaluation for ≥GG2 and ≥GG3 PCa, there was no significant difference in performance of bpMRI nomogram models compared to mpMRI models.Overall, our results suggest that with our current biopsy practices, bpMRI can be a reasonable alternative to mpMRI and may be further considered for clinical adoption within the US.
There is limited data on the granular csPCa detection rates stratifying by DCE.We found that patients classified as PIRADS 4 on mpMRI (PIRADS v2.1) were a heterogeneous group depending on DCE with csPCa detection of 31% for 3+, 41.5% for 4À, and 65.9% for 4+ lesions.PIRADS 4 lesions upgraded by DCE (3+) also had higher csPCa detection rates than patients with PIRADS 3À (19% vs. 31%).Greer and colleagues evaluated concordance of DCE positive and negative lesions with csPCa on whole mount radical prostatectomy (RP) specimens, finding that there were higher rates of csPCa when stratifying by DCE (67.8% DCE positive PIRADS 3 vs 40% DCE negative PIRADS 3, p = 0.02). 13In contrast, Choi and colleagues report no significant difference between PIRADS 3 DCE positive versus negative lesions on whole mount RP specimens. 14These two small series were limited to patients receiving RP for previously diagnosed prostate cancer, which may not translate to patients undergoing prostate biopsy for initial diagnosis.In our study, we found that DCE positivity was associated with increased csPCa detection rates among patients with PIRADS 3-5 PZ lesions.
However, when making decisions regarding clinical practice, one must consider the wider population that is being evaluated with a risk stratification tool.When nomogram models were generated in the wider biopsy naïve population, there was no significant difference in csPCa and ≥GG3 detection comparing bpMRI and mpMRI models, which is consistent with prior studies.One study that evaluated 497 patients from the PROMIS trial found that performance of bpMRI and mpMRI was similar, with no cases of ≥GG3 PCa missed with bpMRI while utilizing detailed transperineal prostate mapping. 15Similar findings were reported from the Goteborg prostate cancer screening 2 trial where cancer detection relying on positivity of bpMRI was non-inferior to mpMRI (15.1% vs. 15.2%). 16Prior metanalyses have conflicting results on sensitivity and performance of bpMRI and mpMRI due to a high degree of heterogeneity in patient populations, outcomes, and study design. 17,18However, there are a number of considerations with implementing bpMRI, such as biopsy decision for PIRADS 3 lesions, reader experience, image quality, patient selection, and pre-test probability of csPCa.
Decision to biopsy PIRADS 3 lesions remains controversial as csPCa detection rates vary from 12% to 23.9%, and as a result practice patterns vary widely. 2,19,20In general, for providers following a biopsy-all approach based on a positive MRI (PIRADS 3-5), detection rates for bpMRI and mpMRI will be the same based on the PIR-ADS v2.1 grading system.DCE is less relevant to initially identifying a lesion as it is to modifying the relative degree of suspicion for men with a known lesion.At our institution, 77% of PIRADS 3 lesions in biopsy naïve patients were biopsied in a diagnostic pathway with PHI prior to mpMRI, and using these practice patterns, and the risk calculators showed no difference in bpMRI and mpMRI performance. 10However, for providers who are less inclined to biopsy PIRADS 3 lesions, implementation of bpMRI may make forgoing biopsy more difficult and increase biopsy rates of PIRADS 3 lesions.
Our findings must be interpreted in the context of differential performance of bpMRI and mpMRI based on reader experience and image quality.There is a significant range in positive predictive value for PIRADS ≥3 lesions even with mpMRI images across centres, individual radiologists, and by biopsy performance by urologists. 21,22The utility of DCE may differ by reader experience level with less relevance for more experienced readers but important to optimize sensitivity among less experienced readers.
PIRADS DWI 3 patients upgraded by DCE to PIRADS 4 (called 3+) and PIRADS DWI 3 lesions with negative DCE (called 3À) are especially relevant for comparing bpMRI and mpMRI.Therefore, we sought to (1) determine the association of DCE with csPCa detection by comparing risk-stratification based on bpMRI, mpMRI (PIRADS v2.1), and a fully DCE stratified approach among patients with their highest PIRADS lesion in the PZ.Additionally, we evaluate (2) the impact of DCE on individualized risk calculation for all-comers receiving MRI prior to biopsy by developing bpMRI-based nomograms and comparing performance to previously developed mpMRI-based nomograms. 102 | SUBJECTS/PATIENTS AND METHODS 2.1 | Study populations 2.1.1 | Evaluation of DCE for csPCa detection in PZ PIRADS lesions Between March 2018 and February 2022, we identified biopsy naïve patients who underwent pre-biopsy MRI evaluated across the eleven hospital Northwestern Medicine healthcare system with IRB approval (STU00214996).The initial cohort of interest included patients receiving mpMRI before prostate biopsy with the highest PIRADS lesion in the PZ (PIRADS 3-5).Patients with transitional zone lesions as their highest PIRADS score, as well as patients with PIRADS 1 and 2 findings were excluded from the initial analysis.Patients with noncontrast MRI study (n = 46), lack of DWI rating due to poor imaging quality (n = 23), or discrepancies in individual MRI series and final PIR-ADS rating (i.e.DWI score of 3 with positive DCE in PZ but PIRADS 3 recorded on final impression, n = 33) were excluded.
were determined per provider preference.Pathology reports were reviewed for highest Gleason Grade and reported by highest International Society of Urological Pathology (ISUP) Gleason Grading system.Patients were categorized by overall highest Gleason Grade Group.

F I G U R E 1
Categorization of (A) peripheral zone and transitional zone lesions with PI-RADS v2.1 and (B) detection of csPCa by DWI score and full DCE stratification.
range (IQR).Mann-Whitney U, Pearson's T test, and Chi squared tests were used to compare descriptive characteristics.Univariable and multivariable logistic regressions were performed to determine factors associated with csPCa detection.Total PSA and prostate volume were excluded from multivariable regression due to collinearity with prostate-specific antigen density (PSAD).Indicator terms were utilized to compare DCE positive and negative lesions.To test discrimination, area under the curve (AUC) from receiver operating characteristic (ROC) curves were compared.Statistical significance was defined at p value <0.05, and statistical analyses were performed with R (version 4.2.1).For nomogram generation, univariable and multivariable logistic regression models were used to identify factors associated with ≥GG2 and ≥GG3 prostate cancer for inclusion in nomogram using both biparametric and multiparametric parameters.ROC curves were generated, and DeLong's test was used to compare performance of bpMRI versus pMRI parameters.We then assessed our nomograms in the independent validation cohort, performing DCA and evaluating calibration of the model with Brier scores, Cox intercept, Cox slope, and Spiegelhalter Z statistics.
T A B L E 1 Baseline characteristics stratified by csPCa.Univariable and multivariable analysis of factors associated with csPCa with mpMRI PIRADS stratified by dynamic contrast enhancement across PIRADS DWI 3 patients (3À and 3+).DeLong comparison of ROC models for mpMRI and bpMRI models for validation Cohort.
25e PIRADS steering committee released a commentary on bpMRI for biopsy naïve men, recommending initial risk stratification as low risk and very high risk patients may not benefit from contrast studies.25Patientsatlow risk of csPCa will have high probability of negative MRI, and patients at high risk of csPCa with evidence of locally advanced cancers by DRE or with significantly elevated PSAs will almost certainly have MRI lesions and subsequently undergo biopsy.Contrast administration is most likely to have utility in patients with intermediate risk for csPCa, prior negative biopsies with unexplained persistent PSA elevations, and patients undergoing active surveillance with concerning PSA kinetics.In these cases, DCE may improve reader confidence, decrease number of indeterminate cases, and help guide MRI-guided biopsy particularly for smaller lesions.First, our study is limited by its retrospective cohort design.We attempted to minimize selection bias by including all biopsy naïve patients evaluated by prostate MRI, including those who were not biopsied and those with negative MRIs, to understand the broader implications of bpMRI.Second, readers were not blinded to DCE series, as the series was based on individual series ratings on radiology reports among patients who all underwent mpMRI.Our hospital system includes a mix of community hospitals and high volume readers, but as discussed, reader experience affects the discriminative ability of prostate MRI.Third, while our nomograms were validated with an independent institutional cohort, further external validation of our models is required to evaluate generalizability.This is especially relevant to test performance across a large cohort of MRI readers with variations in reading experience and volume.
23,24Additionally, image quality becomes paramount with omission of DCE, and healthcare systems that attempt to incorporate bpMRI will need to implement recall or on-table monitoring to ensure that T2 and DWI images are of sufficient quality.Incorporation of bpMRI may be more feasible at high volume MRI centres and in healthcare systems with a robust imaging quality control and patient recall protocols in place.Furthermore, patient selection based on pre-test probability for csPCa and imaging indication is important for implementation of bpMRI.